Rethinking first-line progestin use in endometriosis: a comparative therapeutic review and future-ready drug delivery perspective

Endometriosis is a chronic, relapsing inflammatory disease requiring sustained hormonal suppression, yet first-line management remains dominated by daily oral progestins designed for short-acting use. Although pharmacologically effective, long-term outcomes are frequently compromised by fluctuating exposure, tolerability-driven discontinuation, and poor persistence. This narrative comparative review examines first-line progestins across efficacy, safety, tolerability, and persistence, alongside long-acting platforms including intrauterine systems, vaginal rings, implants, injectables, and emerging depots. Relevant clinical, pharmacokinetic, adherence, formulation, and preclinical evidence was identified through iterative literature searches. By synthesizing clinical, pharmacokinetic, and adherence evidence within a unified translational framework, we identify formulation-driven gaps that may influence exposure stability and therapeutic durability. The analysis distinguishes delivery-modifiable constraints from biological limitations such as progesterone resistance and disease heterogeneity, and outlines priorities for next-generation formulation development. Aligning delivery architecture with disease chronicity may offer a pragmatic, scalable, and clinically impactful pathway to strengthen established progestin therapies while complementing molecular innovation. Interpretation is limited by heterogeneity in study populations, endpoints, and treatment durations, and by limited endometriosis-specific clinical evidence for several emerging delivery platforms. Similar content being viewed by others Long-term endometriosis treatment is influenced not only by the choice of progestin but also by treatment burden, tolerability, and the ability to maintain therapy over time. | | Delivery design represents an underexplored opportunity to improve the durability of established progestin therapies. | | Future research should compare long-acting and oral progestins over longer treatment periods to determine whether more consistent delivery improves treatment persistence and patient outcomes. |

Endometriosis is a chronic gynecological disorder in which tissue resembling the endometrial lining proliferates outside the uterine cavity. Globally, it affects approximately 10–15% of women of reproductive age, amounting to approximately 200 million individuals, which is estimated to reach 220 million by 2050 (a further increase by 10%) [1,2,3]. Contemporary global burden estimates further quantify this trajectory, showing a 10.37% rise in incident cases and a 16.36% rise in disability-adjusted life-years from 1990 to 2019 [4]. Despite this substantial disease burden, diagnosis is frequently delayed by 7–10 years [5], and it is commonly dismissed as “just painful periods” rather than recognized as manifestations of a systemic, inflammatory, and immune-modulated disease. A recent international synthesis reports a mean diagnostic delay of ~ 6.8 years (cross country range 1.5–11.4 years), implicating patient-, provider-, and system-level factors [6]. Clinically, endometriosis is characterized by chronic pelvic pain, dysmenorrhea, and subfertility, leading to profound psychosocial and economic consequences, including impaired productivity and increased prevalence of anxiety and depression [3, 7]. Given its relapsing course and cumulative burden, effective management requires long-term strategies that sustain symptom control, suppress ectopic lesions, and preserve fertility [8]. International guidelines, including the European Society of Human Reproduction and Embryology (ESHRE) guideline on Endometriosis (2022) [9], the National Institute for health and Care Excellence (NICE) Guideline NG73 [10], and the American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin No. 114 [11], recommend individualized hormonal therapy as first-line management. Combined oral contraceptives (COCs), progestins, and gonadotropin-releasing hormone (GnRH) analogs remain central to this approach. However, real-world effectiveness is frequently undermined by tolerability issues, hypoestrogenic adverse effects, fertility considerations, and high rates of treatment discontinuation with daily or cyclic regimens [12, 13]. Adherence erosion driven by pill burden, stigma, treatment fatigue, and health system barriers is now recognized as a major determinant of long-term failure, particularly among adolescents and resource-limited populations [14, 15]. These gaps underscore that therapeutic success in endometriosis extends beyond pharmacologic potency alone. Among the available options, progestins occupy a unique position owing to their multifaceted pharmacology. They suppress ovulation, induce decidualization and atrophy of ectopic implants, and modulate inflammatory and immune pathways implicated in disease persistence [12, 16]. Their availability across oral, injectable, intrauterine, and implantable platforms supports their use as cost-effective, fertility-preserving therapies suitable for prolonged administration [13, 17]. However, the clinical response remains heterogeneous, with relapses, breakthrough bleeding, and intolerance driving discontinuation and variable outcomes in a substantial proportion of patients. Several recent reviews have evaluated the clinical efficacy, safety profiles, and comparative performance of individual progestins in endometriosis. Others have discussed emerging molecular therapies or summarized guideline recommendations. However, few have systematically integrated pharmacologic mechanisms, real-world persistence data, and formulation architecture within a unified therapeutic-durability framework. This review advances a delivery-centric framework, arguing that limitations in long-term therapeutic durability may arise from the combined effects of disease biology, pharmacological response, treatment burden, and short-acting dosing paradigms. By integrating pharmacology, pharmaceutics, and clinical evidence, we critically compare first-line progestins in terms of efficacy, safety, tolerability, and real-world adherence, with a particular emphasis on how delivery architecture shapes clinical performance. Through this translational lens, we delineate formulation-driven gaps, pharmacokinetic constraints, and development priorities that are central to repositioning progestins toward sustained, patient-centered disease control, thereby defining a pragmatic roadmap for pharmaceutical innovation in endometriosis management. Literature search and evidence selection This review was undertaken as a narrative comparative review, with relevant literature identified through iterative literature searches. Searches were guided by the objectives of the review and used combinations of terms related to “endometriosis,” “progestins/progestogens,” individual progestin agents, “efficacy,” “pain,” “adherence,” “persistence,” “discontinuation,” “long-acting delivery,” “sustained release,” “vaginal ring,” “intrauterine system,” “implant,” and other relevant drug-delivery concepts. Searches were also tailored to individual progestins and delivery platforms where more specific evidence was required. No predefined publication-year limit was applied, allowing both established and more recent evidence to be considered. Clinical trials, observational studies, systematic reviews and meta-analyses, clinical guidelines, pharmacokinetic studies, and relevant formulation, drug-delivery, and preclinical studies were considered according to their relevance to the topic. Additional relevant publications were identified by examining the reference lists of key articles. Where endometriosis-specific evidence was limited, evidence from postoperative management, contraception, and preclinical or translational drug-delivery studies was considered to provide context for treatment durability and future formulation development; such evidence was interpreted as translational support rather than as direct evidence of first-line efficacy in endometriosis. Given the broad and heterogeneous nature of the available evidence, findings were integrated narratively, with emphasis on clinical outcomes, treatment persistence, pharmacokinetic considerations, and the potential role of drug-delivery strategies in improving the long-term use of progestin therapy. Pathophysiology and hormonal targets in endometriosis Endometriosis is an estrogen-driven inflammatory disorder characterized by ectopic endometrial-like tissue within pelvic and extrapelvic sites [18]. Lesion establishment cannot be explained by retrograde menstruation alone and reflects a convergence of immune dysfunction, altered tissue repair, and aberrant hormonal signaling [19]. At the tissue level, local estrogen biosynthesis through aromatase (CYP19A1), steroid sulfatase (STS), and 17β-hydroxysteroid dehydrogenase (17β-HSD) pathways supports lesion growth and varies by lesion phenotype (superficial, ovarian endometrioma, deep infiltrating), underscoring site-specific microenvironments that amplify estradiol availability [20]. Concurrent estrogen receptor (ER) imbalance (increased ERβ and decreased ERα expression) and progesterone receptor (PR) dysregulation, particularly reduced PR expression, contribute to progesterone resistance and weaken anti-inflammatory and antiproliferative responses [21, 22]. Epigenetic mechanisms (e.g., differential DNA methylation and chromatin remodeling) further modulate steroid signaling and immune genes in eutopic and ectopic tissue, reinforcing estrogen dominance and impaired progesterone action [12, 16, 23]. These molecular features define therapeutic targets for hormonal intervention. Progestins suppress ovulation, oppose estrogen driven transcription, and modulate inflammatory mediators central to lesion survival, whereas combined oral contraceptives and GnRH analogs act primarily through systemic estrogen reduction [13, 17]. Clinical guidelines therefore emphasize sustained hormonal suppression for long-term disease control, particularly following surgery or in patients with recurrent disease [9,10,11]. However, biological heterogeneity and variable progesterone responsiveness mean that therapeutic success depends not only on target engagement but also on maintaining continuous, tissue-relevant exposure. These molecular and phenotypic differences contribute to variable progestin responsiveness, with progesterone resistance representing an important biological limitation to treatment response. (Fig. 1). Current first-line therapies: a comparative overview Progestins are the mainstay of endometriosis therapy, with efficacy and tolerability shaped by chemical class, receptor binding, pharmacokinetics, and formulation. Differences in bioavailability, half-life, and metabolic or androgenic effects influence pain relief, bone health, and adherence. Dosage forms, such as oral, injectable, intrauterine, or implantable, further affect patient experience. Table 1 summarizes the key features of commonly used progestins to support individualized treatment and guide future drug-delivery strategies. The comparison focuses primarily on evidence generated in endometriosis; where direct evidence is limited, pharmacological, pharmacokinetic, or formulation-related information from other indications is presented for context rather than as evidence of efficacy in endometriosis. In summary, while all progestins act through PR-mediated suppression, their clinical profiles differ significantly. Dienogest combines robust pain efficacy with a generally favorable bone-safety profile, the levonorgestrel releasing intrauterine system (LNG-IUS) minimizes systemic exposure with strong local effects, norethindrone-acetate offers potent symptom control but with androgenic liabilities, and depot medroxyprogesterone-acetate DMPA is effective but is associated with bone mineral density (BMD) loss. Thus, the choice of agent must balance efficacy, tolerability, and long-term safety, with growing emphasis on long-acting delivery systems for sustained management. Gaps and challenges in current therapy Despite their demonstrated efficacy in controlled settings, progestin-based therapies may underperform in real-world endometriosis management for several reasons, including adverse effects, pharmacokinetic variability, incomplete biological responsiveness such as progesterone resistance, and barriers to sustained treatment. These factors may interact with disease phenotype and patient characteristics, making treatment response highly variable. These factors collectively undermine long-term disease control in a condition that demands continuous hormonal suppression. Real-world healthcare utilization data also show a persistent burden of hospitalizations after diagnosis, underscoring the need for durable medical control in this area [44]. Daily oral therapy in endometriosis: a real-world compliance barrier Oral progestins and COCs are widely used first-line therapies because of their capacity to suppress ovulation and counter estrogen-driven disease activity [12, 16, 17]. However, daily oral dosing introduces substantial pharmacokinetic variability, and missed or delayed doses may precipitate a rapid decline in drug concentrations, resulting in inconsistent progesterone receptor engagement and fluctuating symptom control. Real-world adherence is challenged by irregular routines, stigma associated with hormonal therapy, competing responsibilities, and treatment fatigue across age groups [15]. Mood-related adverse effects further contribute to oral contraceptive discontinuation in endometriosis cohorts [45]. These dynamics may contribute to inconsistent drug exposure and symptom control, particularly during chronic treatment [46] as illustrated in Fig 2. Real-world discontinuation rates approaching 37% across agents underscore that daily dosing is not merely a behavioral issue but also a determinant of therapeutic inconsistency [47, 48]. Even agents with strong efficacy profiles, such as dienogest, show attenuated benefits when adherence is compromised, whereas user-independent systems maintain higher continuation (e.g., LNG IUD 92% at 1 year in adolescents) [49]. Risk of breakthrough bleeding Breakthrough bleeding (BTB) is among the most frequent and disruptive adverse effects of progestin-only and combined hormonal therapies [12, 13, 16, 48]. Although not typically medically serious, the BTB materially affects quality of life and remains a leading cause of early discontinuation [48, 50]. Retrospective analyses identify spotting as a primary driver of cessation, particularly among COC users [42]. Mechanistically, BTB reflects endometrial instability under sustained hormonal exposure and is influenced by dose, delivery modality, interindividual endometrial responsiveness, and exposure fluctuations. In implants, lower systemic etonogestrel levels correlate with more bleeding irregularity, highlighting sensitivity to exposure stability [51]. Limited long-term data for chronic disease management A persistent gap in the evidence base is the lack of long-duration clinical trials as most studies evaluating hormonal therapies in endometriosis do not exceed 1 year [48, 50], Notable exceptions (e.g., a 3-year pragmatic RCT) inform durability endpoints but do not eliminate broader evidence gaps [46]. Similarly, evidence for LNG IUD as disease-modifying therapy after surgery shows potential benefits but remains limited and low certainty in systematic reviews [52]. These constraints limit confident counseling on long-term safety, metabolic effects, bone health, fertility outcomes, and durability of symptom relief. Discontinuation rates Discontinuation remains a defining challenge in endometriosis therapy. One study reported an overall medical treatment discontinuation rate of 53.6%, with COCs carrying the highest risk [42]. Among progestins, reported discontinuation rates range from 0 to 37.1%, driven by adverse effects, persistent pain, or perceived lack of efficacy [42, 48, 53]. These attrition patterns translate directly into symptom recurrence, lesion progression, and increased healthcare utilization. Long-term clinical trials, claims, and real-world datasets collectively show high attrition and repeat healthcare contact (including surgeries), reinforcing the need for delivery strategies that promote persistence [44, 46]. Adherence issues in adolescents and rural settings Adherence and continuity-of-care challenges may be particularly relevant in adolescents and rural communities, although endometriosis-specific evidence remains limited [54]. In adolescents, inconsistent routines, limited health literacy, and psychosocial stigma surrounding hormonal use may impair persistence with long-term treatment [55]. Whereas user-independent options can mitigate some adolescent adherence barriers (e.g., 92% 1-year LNG IUD use continuation in adolescents) [49], bone health is an additional consideration in adolescents, particularly when selecting therapies associated with sustained hypoestrogenism, given the importance of this period for peak bone mass accrual [39]. System-level constraints remain significant. In rural settings, limited specialist access, supply constraints, and fragmented follow-up may further pose additional challenges to the management of chronic gynecological conditions [10, 56]. Population-level data also reveal urban–rural differences in endometriosis-related care utilization, with higher hospitalization rates in major cities versus remote areas, pointing to access and pathway disparities [44]. Patient-reported outcomes and satisfaction While reductions in pain scores are commonly reported, patient-reported outcomes remain inconsistently captured. Systematic reviews indicate that quality of life, treatment acceptability, and satisfaction are often underreported despite their central relevance in chronic disease management [57,58,59]. Notably, even with clinical improvement, side effects and daily treatment burden contribute to dissatisfaction; median satisfaction with progestin therapy is approximately 62%, with 27% of patients remaining dissatisfied [57]. These findings highlight the disconnect between traditional efficacy endpoints and patient priorities. Need for sustained and long-acting progestin formulations Why focus on progestins in endometriosis? Progestins remain the backbone of medical management in endometriosis and are consistently recommended by ESHRE, ACOG, and NICE because of their ability to induce decidualization, suppress ovulation, and counter estrogen-driven inflammation [9,10,11]. Current evidence syntheses for clinical practice reaffirm progestins as first-line options for pain control across phenotypes and life stages, emphasizing individualized selection and, when appropriate, long-term suppression. Mechanistically, progestins oppose local estrogen action and modulate inflammatory pathways, supporting broad utility from adolescents to patients with estrogen contraindications [60]. Compared with GnRH analogs, which often require add-back therapy and raise concerns regarding bone health, or COCs, which are not universally tolerated, progestins offer a more flexible and sustainable therapeutic profile [48, 50, 61]. Accordingly, the translational opportunity lies less in inventing new hormonal classes than in optimizing delivery of established progestins to sustain disease control over years. Meta-analytic and cohort data with long-acting systems reinforce this direction by demonstrating durable symptom relief and lower recurrence after surgery in selected populations [62]. Chronic disease, daily pills: a misaligned strategy Endometriosis is a lifelong, relapsing condition that often begins in adolescence and persists for decades. Despite this, daily oral dosing remains the dominant treatment paradigm. Real-world evidence indicates that continuous therapy is frequently disrupted by lifestyle variability, psychosocial factors, and treatment fatigue [15, 47, 48]. Importantly, discontinuation of progestin therapy is associated with increased symptom recurrence and higher rates of repeat surgical intervention [63, 64]. Evidence from systematic reviews and controlled studies indicates that user-independent, long-acting regimens (e.g., an LNG-IUS as maintenance therapy) can reduce symptom recurrence and maintain benefit over multiyear horizons, supporting durability advantages when exposure is decoupled from daily behavior. These findings suggest that daily dosing may add to the challenges of long-term treatment. Long-acting delivery could reduce this burden and provide more consistent exposure, although its benefits may vary across patients and disease phenotypes [62]. The translational rationale underpinning the shift from short-acting oral regimens to long-acting progestin delivery is summarized in Box 1 and Fig. 3. Delivery design as a determinant of long-term effectiveness Adherence is a major determinant of real-world therapeutic durability. Continuation differs strikingly by modality: in a > 5-year maintenance cohort, 91.5% of patients remained on LNG-IUS versus 21.9% on oral regimens (COCs or dienogest), with comparable pain control and fewer systemic side effects in the IUS group [65]. In addition to persistence, delivery format influences clinical outcomes: in the PRE-EMPT trial, long-acting progestogen methods significantly reduced the number of repeat surgical interventions relative to oral contraceptives (73 versus 97 interventions; hazard ratio (HR) 0.67) [46]. These data underscore key translational insight: sustained exposure achieved through delivery design can meaningfully alter disease trajectories, independent of active molecule selection. Systemic exposure and tolerability considerations Systemic adverse effects, including mood changes, bloating, and weight gain, remain the leading causes of progestin discontinuation [12, 13, 16, 17]. Long-acting systems such as the LNG-IUS demonstrate lower systemic exposure and improved tolerability profiles [46, 65], likely reflecting reduced peak-to-trough fluctuations. Lower systemic exposure with the LNG-IUS has translated to favorable long-term tolerability alongside stable pain control [65]. Emerging delivery approaches (e.g., intravaginal rings combining an aromatase inhibitor ± progestin) show programmable release and acceptable safety/tolerability in early studies, supporting tissue-targeted strategies while preserving efficacy [66]. From a pharmaceutical standpoint, long-acting delivery is therefore both an adherence solution and a way to optimize the exposure–response relationship. Translational lessons from long-acting reversible contraception User-independent delivery systems have consistently demonstrated superior continuation and real-world effectiveness in contraception. The CHOICE Project reported over 86% 1-year continuation for implants and intrauterine systems, compared with less than 60% for daily oral methods [67, 68]. In endometriosis, similar patterns have emerged: 5-year registry data show markedly greater continuation with LNG-IUS than with oral dienogest or COCs (91.5% versus 21.9%) [65]. These data provide a validated translational framework, demonstrating that sustained hormonal suppression may be better supported through delivery systems that minimize reliance on daily patient behavior. Formulation opportunities: a pharmaceutics perspective From a pharmaceutical standpoint, progestins possess physicochemical and pharmacodynamic attributes that make them particularly amenable to long-acting and site-directed delivery. These properties have been successfully exploited in contraception and provide a useful translational foundation for endometriosis, where therapeutic durability and consistent treatment exposure remain important therapeutic considerations. Accordingly, current innovation is less about introducing new hormones and more about refining delivery architectures to potentially optimize exposure, reduce systemic burden, and extend therapeutic continuity using platforms with established clinical precedent (Fig. 4). The delivery platforms discussed below (see also Table 2) vary in the extent of endometriosis-specific evidence; established clinical approaches are considered alongside contraceptive and preclinical platforms primarily to illustrate translational feasibility and opportunities for future development. Evidence from contraception, other indications, and preclinical models is therefore considered as supportive of platform feasibility or translational potential rather than as direct evidence of efficacy in endometriosis. The following platforms are not presented as technological alternatives alone, but as delivery architectures whose design characteristics may address some of the durability constraints identified in Sections "Gaps and challenges in current therapy" and "Need for sustained and long-acting progestin formulations". Intrauterine systems (IUS) The LNG-IUS remains the most clinically mature long-acting progestin platform, delivering localized hormone exposure with minimal systemic absorption and favorable tolerability [46, 65]. Its clinical experience in endometriosis provides an important reference point for evaluating the potential contribution of sustained local delivery to treatment durability [12, 17]. Updated labeling now supports contraceptive use for up to 8 years with a declining in vivo release rate (~ 21 µg/day at 24 days, ~ 11 µg/day at 5 years, ~ 7 µg/day at 8 years), illustrating engineered control of dose delivery. Extended use data also demonstrate sustained contraceptive performance and acceptable bleeding profiles, illustrating the feasibility of prolonged controlled delivery [69]. In addition to commercial devices, danazol-loaded IUSs have demonstrated controlled release and anti-inflammatory activity in preclinical models [70]. Structural innovations such as frameless designs (e.g., FibroPlant®) aim to reduce expulsion and bleeding irregularities, illustrating how device engineering and release modulation may expand the applicability of long-acting delivery systems [71]. Vaginal rings Vaginal rings offer a polymer-based platform for continuous hormone delivery via vaginal absorption, avoiding hepatic first-pass metabolism [72]. While originally developed for contraception, their relevance to endometriosis lies in tunable release kinetics and user-controlled dosing. Clinical experience suggests potential benefit in patients with rectovaginal disease, although bleeding irregularities have limited acceptance [73]. Advanced designs, including danazol-loaded rings and systems delivering anastrozole with or without levonorgestrel, have shown lesion suppression and pain reduction with lower systemic exposure in preclinical and early clinical studies [66, 74, 75]. The modularity of these devices positions vaginal rings as adaptable platforms rather than fixed-dose devices. Subdermal implants Subdermal implants can provide highly predictable systemic exposure over extended periods and eliminate the need for daily dosing [76, 77]. Although not formally approved for endometriosis, clinical studies report reductions in pain, improvement in quality of life, and continuation rates approaching 93% at 2 years [78, 79]. From a platform standpoint, the etonogestrel implant delivers 68 mg from a single radiopaque rod with a validated 3-year duration, offering highly reliable user-independent delivery [80]. These findings demonstrate the feasibility of prolonged, user-independent delivery in endometriosis and provide a rationale for further evaluation of whether exposure stability and longer dosing intervals translate into improved therapeutic durability. Injectable microparticles/manoparticles Biodegradable injectable systems enable sustained delivery while allowing formulation-level control over release kinetics and tissue distribution. Levonorgestrel-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres maintained therapeutic concentrations and suppressed cyst growth for up to 6 months in animal models without systemic effects [81]. Nanoparticle platforms further extend this concept by co-delivering antioxidative or antiangiogenic agents, such as epigallocatechin gallate–doxycycline PLGA systems or nanoceria, resulting in lesion regression through complementary disease-modifying mechanisms [82, 83]. These findings demonstrate formulation and pharmacological feasibility in preclinical models, but their clinical relevance to endometriosis remains to be established. Biodegradable in situ forming implants (ISFIs) ISFIs solidify after injection, creating biodegradable depots with programmable release profiles [84, 85]. Their clinical use in other chronic conditions (Eligard®, Atridox®, and Sublocade®) demonstrates the feasibility of biodegradable depot systems and provides a translational precedent [86]. For endometriosis, ISFIs could offer a minimally invasive means to sustain progestin exposure over months, and may help in addressing the limitations of short-acting regimens [13]. Early levonorgestrel ISFI studies demonstrated controlled release and durability [87, 88], with tunable degradation enabling individualized dosing horizons [78]. Transdermal patches Transdermal delivery provides a noninvasive route that avoids first-pass metabolism and may support extended dosing intervals [89]. However, existing contraceptive patches achieve relatively low steady-state progestin levels and are limited by skin reactions and detachment [90, 91]. Emerging strategies, including permeation enhancers, nanocarriers, advanced adhesives, and microneedle-assisted transport, aim to overcome these constraints [92]. While still exploratory, these approaches may enable future transdermal systems to achieve exposure profiles suitable for chronic endometriosis management. Challenges in translating progestins for first-line use in endometriosis Despite their established therapeutic value, translating progestins into reliable first-line, disease-modifying therapies for endometriosis requires addressing a focused set of unresolved biological, pharmacokinetic, and regulatory constraints. These challenges reflect intrinsic features of endometriosis biology and current drug-development paradigms, rather than shortcomings of progestin pharmacology itself. Progesterone resistance as a biological ceiling Progesterone resistance represents the dominant biological constraint on progestin efficacy. Altered progesterone receptor B:A (PR-B/PR-A) ratios, epigenetic silencing of PR-B, progesterone-antagonistic inflammatory cytokines, and dysregulated stromal–immune interactions collectively blunt responsiveness to both endogenous progesterone and exogenous progestogens [93]. Clinically, this contributes to incomplete pain control in up to one-third of patients [94]. Importantly, progesterone resistance defines a biological ceiling beyond which improvements in dose, exposure duration, or formulation alone are unlikely to yield additional benefit, underscoring the need for adjunctive or combination strategies. Limits of formulation-led optimization Advanced delivery platforms can stabilize systemic or local drug exposure but cannot correct receptor-level dysfunction. In patients with partially preserved progesterone signaling, controlled-release systems may improve consistency of pharmacodynamic engagement by reducing exposure variability [95, 96]. However, therapeutic benefit remains contingent on intact intracellular pathways, emphasizing that formulation innovation must be aligned with disease biology rather than pursued as a standalone solution. Evidence gaps for indication-specific use While vaginal rings, implants, and patches are well characterized in contraception, endometriosis-specific evidence remains limited. Existing studies are frequently underpowered, short in duration, and heterogeneous in endpoint selection, with few direct comparisons against standard oral progestins [97]. The absence of long-term, indication-specific trials restricts the precise positioning of these systems within first-line treatment algorithms. Dose and release profile constraints Endometriosis requires sustained suppression of inflammatory and nociceptive pathways, yet progestins operate within a narrow therapeutic window. Underexposure risks lesion persistence, whereas higher systemic levels increase bleeding irregularities, mood symptoms, and metabolic effects [51]. Release profiles optimized for ovulation suppression may not adequately address the pharmacodynamic requirements of deep fibrotic or infiltrative disease [80, 90, 98]. Therefore, achieving peak-free, tissue-relevant exposure remains a central formulation challenge. Disease heterogeneity and therapeutic responsiveness Endometriosis comprises biologically distinct phenotypes with variable vascularity, fibrosis, and hormone receptor expression [99]. Deep infiltrating disease shows greater vascularization and differs molecularly from superficial disease; hormonal suppression can limit progression in many but not all cases, highlighting phenotype-specific responsiveness and the need for adaptable delivery strategies [97]. Compared with ovarian endometriomas, deep infiltrating disease is associated with greater pain severity and reduced hormonal sensitivity [53, 100]. This heterogeneity complicates dose selection and limits flexibility once long-acting systems are deployed, highlighting the need for phenotype-informed delivery strategies. Regulatory and translational gaps Most progestin delivery platforms were developed for contraception rather than chronic inflammatory disease. Current Food and Drug Administration (FDA) patient-focused guidance emphasizes selecting or developing “fit for purpose” clinical outcome assessments (COAs) centered on what matters to patients (e.g., pain interference, function), yet endometriosis-specific COAs and durability endpoints are still being standardized [101]. Concurrently, FDA real-world data (RWD) guidance delineates how eletronic health record (EHR) and claims data can support regulatory decision-making, offering pathways to evaluate long-term safety and effectiveness beyond short trials capabilities that remain underused in endometriosis drug delivery studies [102]. The absence of harmonized measures for pain durability, lesion stabilization, and quality of life outcomes continues to slow translation from contraceptive adaptation to disease-directed approval [58, 101]. Future directions and research agenda Although progestins are established components of endometriosis management, key uncertainties persist regarding optimal delivery, long-term effectiveness, and real-world performance. Experience with long-acting reversible contraception and the pharmacologic suitability of agents such as dienogest and LNG-IUS demonstrate their technical feasibility for sustained delivery; however, disease-specific validation remains limited [50]. Addressing these gaps requires a coordinated research strategy that integrates comparative clinical evaluation, patient-centered outcomes, and regulatory alignment tailored to a chronic, heterogeneous condition [103, 104]. Call for head-to-head trials Future randomized controlled trials should directly compare emerging long-acting platforms such as vaginal rings, subdermal implants, and injectable depots with standard oral progestins and LNG-IUSs. Primary endpoints must reflect chronic disease management, including durable pain control, lesion stability where assessable, and treatment continuation over multiyear horizons. The incorporation of pharmacokinetic and pharmacodynamic substudies will be critical for linking release profiles with efficacy and tolerability, addressing a persistent limitation of the current evidence base [103, 104]. Integration of patient-reported outcomes Clinical efficacy alone is insufficient to guide first-line therapy selection in patients with a lifelong condition. Future studies should systematically incorporate validated patient-reported outcome instruments to capture treatment acceptability, functional impact, sexual health, and drivers of discontinuation. Tools such as the Endometriosis Daily Diary and established outcome measure frameworks enable standardized assessment across trials and registries. Dedicated research in adolescents and underserved populations is essential to address disparities in persistence and access [105, 106]. Regulatory pathways and real-world evidence (RWE) integration Regulatory approvals in endometriosis have relied predominantly on traditional randomized trials, as exemplified by Elagolix, Relugolix, and Linzagolix [9]. Real-world evidence is increasingly recognized as a complementary source for evaluating long-term safety, fertility outcomes, adherence, quality of life, and health-economic impact [107]. While such data have influenced accelerated decisions in oncology [108], their principal role in endometriosis is likely postapproval, supporting life-cycle management and reimbursement. Regulatory agencies, including the US Food and Drug Administration, encourage the structured use of patient registries, electronic health records, and pragmatic data sources to strengthen these pathways [102]. Target product profile (TPP) as a development framework The development of first-line long-acting progestin therapies should be guided by a clearly defined TPP (Table 3) that prioritizes peak-free exposure, sustained symptom control, long-term tolerability, and patient acceptability. Aligning formulation design with this framework provides a pragmatic pathway to translate sustained-release concepts into clinically and commercially viable therapies.

Endometriosis is a lifelong, relapsing disease that demands therapeutic strategies capable of sustained biological control. However, first-line management continues to rely on daily oral progestins, a dosing paradigm poorly aligned with the realities of chronic inflammatory disease. The evidence reviewed here suggests that therapeutic performance reflects not only progestin pharmacology but also treatment burden, adherence, pharmacokinetic variability, and delivery characteristics. By integrating clinical outcomes, real-world adherence data, and formulation science, this review reframes progestin therapy through a delivery-centric lens. Long-acting platforms may offer advantages beyond convenience by providing more consistent drug exposure, reducing dosing burden, and supporting therapeutic continuity over extended treatment periods. Their success in contraception provides a useful translational precedent, while emerging endometriosis-specific evidence remains limited and heterogeneous. Accordingly, potential effects on relapse, procedural burden, and disparities in care require confirmation in appropriately designed comparative studies. By considering delivery architecture as an important therapeutic determinant alongside pharmacology and disease biology, this framework shifts the strategic focus of first-line progestin therapy from molecule selection toward durability optimization. In a biologically heterogeneous disease where progesterone resistance and variable treatment response may pose therapeutic ceilings, meaningful advances may arise not solely from molecular novelty, but from deploying established agents with greater precision, stability, and alignment to chronic disease management. Future clinical research should prioritize head-to-head comparisons of long-acting and oral progestins, with sufficiently long follow-up to assess sustained pain control, treatment persistence, safety, quality of life, and reproductive outcomes, alongside pharmacokinetic–pharmacodynamic evaluation to determine whether improved exposure translates into meaningful clinical benefit.

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Availability of data and material: Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. Code availability (software application or custom code) Not applicable. Conflict of interest Not applicable. Ethical approval Not applicable. Consent to participate Not applicable. Consent for publication Not applicable. Author contributions Lokesh Yadav: conceptualization, methodology, investigation, data curation, writing—original draft, writing—review and editing. Aniruddha Banerjee: investigation, data curation, writing—review and editing. Akhilesh Patel: investigation, validation, writing—review and editing. Praveen Thaggikuppe Krishnamurthy: validation, supervision, writing—review and editing. Mukesh Nandave: supervision, critical review, writing—review and editing. Sonam Patel: supervision, project administration, writing—review and editing. All authors read and approved the final version. Use of AI-assisted tools During preparation of this manuscript, the authors used ChatGPT (OpenAI) to assist with language editing, sentence structure, and flow only. All AI-assisted output was critically reviewed and revised by the authors, who remain fully responsible for the content, accuracy, interpretation, and final version of the manuscript. Rights and permissions Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/. About this article Cite this article Yadav, L., Banerjee, A., Patel, A. et al. Rethinking first-line progestin use in endometriosis: a comparative therapeutic review and future-ready drug delivery perspective. Drugs Ther Perspect (2026). https://doi.org/10.1007/s40267-026-01282-5 Received: Accepted: Published: Version of record: DOI: https://doi.org/10.1007/s40267-026-01282-5